Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of tuberculosis

ABSTRACT

Described is a composition that includes:(i) a drug against tuberculosis,or a pharmaceutically acceptable salt thereof, and(ii) a compound of Formula II,or a pharmaceutically acceptable salt thereof. The composition is useful in the treatment of tuberculosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/937,851, filed Jul. 24, 2020, which is a continuation of U.S.application Ser. No. 16/091,774, filed Oct. 5, 2018, and granted as U.S.Pat. No. 10,945,999 on Mar. 16, 2021, which is a U.S. National PhaseApplication of International Application No. PCT/IB2017/051999, filedApr. 7, 2017, which claims the benefit of U.S. Provisional ApplicationNo. 62,319,838, filed Apr. 8, 2016, each of which are herebyincorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to ring-fused thiazolino 2-pyridones, toprocesses for preparing such compounds, to their use in treating and/orpreventing tuberculosis infections, to methods for their therapeutic useand to a pharmaceutical composition containing any such compounds. Inparticular, the present disclosure relates to said ring-fused thiazolino2-pyridones in combination with a drug against tuberculosis, to the useof such a combination in treating and/or preventing tuberculosisinfections, to methods for its therapeutic use and to a pharmaceuticalcomposition containing any such combinations.

BACKGROUND

Tuberculosis (TB) infects at least 30% of the world's population. Everyyear there are about 9 million newly infected patients, and about 1.5million deaths. A major roadblock in treating tuberculosis (TB) is therecalcitrance of Mycobacterium tuberculosis (Mtb) to currently availableantibiotics, which necessitates lengthy treatment regimens that do notalways eradicate the tuberculosis bacteria.

The main cause of TB is Mycobacterium tuberculosis (Mtb). However, thereare also other tuberculosis causing mycobacteria such as M. bovis, M.africanum, M. canetti, and M. microti.

Patients suffering from tuberculosis may have active tuberculosis orlatent tuberculosis. Active tuberculosis means that tuberculosisbacteria are reproducing and spreading in the body, causing tissuedamage. A patient infected with active tuberculosis feels sick. Commonsymptoms are cough that does not go away, coughing blood and weightloss. Further, a patient suffering from active tuberculosis isinfectious, i.e. can spread tuberculosis to other people. Thetuberculosis is spread through the air when the patient talks, coughs,sneezes etc.

Latent tuberculosis, which may also be denominated dormant, chronic orpersistent tuberculosis, means that tuberculosis bacteria do notmultiply to detectable levels in the body. Commonly, a person infectedwith latent tuberculosis has no symptoms and is not infectious. Thedormant phase can last for a very long time, even during the whole lifetime of the infected person. However, the tuberculosis infection may bereactivated into active tuberculosis. In particular, this may happen inpatients having an immune system deficiency or taking immunosuppressiveagents.

Exposure to tuberculosis can be detected through a tuberculin skin testor blood test. There is currently no diagnostic test that candistinguish between patients that have been exposed and cleared aninfection versus someone who is latently infected. Active pulmonarytuberculosis is detected through sputum smears or culturing of sputum.

Current treatment and prophylactics of drug susceptible tuberculosis arebased on combination therapies including isoniazid(isonicotinylhydrazide, INH). In the standard clinical practice,isoniazid is used in combination with rifampicin (RIF), ethambutol (EMB)and pyrazinamide (PZA) in a 6 month regimen to treat drug-susceptibleactive Mtb infection. The long duration of antibiotic therapy hasserious side effects, and eradication of tuberculosis bacteria is oftenincomplete. Further, this long-term antibiotic therapy has resulted inthe rise of drug resistant tuberculosis, such as multidrug resistanttuberculosis, which constitutes 3.5% of new tuberculosis cases and 20%of previously treated cases. In addition, people infected with latentMtb are prophylactically treated with 9 months of INH or 12 weeks of INHand rifapentine to prevent reactivation of the bacteria.

Mtb infecting a patient may be divided into so-called nonpersisters andpersisters. While nonpersister bacteria may be eradicated with commonlyused tuberculosis antibiotics, the persisters are tolerant of suchantibiotics. The recalcitrance of Mtb persisters to therapy has led toan increase in drug resistance.

Thus, the frequent lack of complete tuberculosis eradication, drugresistance and/or the long treatment times are major challengesassociated with current tuberculosis treatment.

PCT/EP2015/076578 discloses ring-fused thiazolino 2-pyridones, toprocesses for preparing such compounds, to their use in treating and/orpreventing bacterial infections such as Chlamydia. It is mentioned thatthe ring-fused thiazolino 2-pyridones may be administered in combinationwith another therapeutic agent such as an antibiotic. It is notmentioned to use ring-fused thiazolino 2-pyridones for inhibition ofbiofilm formation or treating tuberculosis.

WO 2014/185853 discloses ring-fused 2-pyridones shown to reduce theinfectivity of Chlamydia. Treatment of tuberculosis is not mentioned.

There is a need for alternative and/or improved treatments oftuberculosis. In particular, there is a need for treatment oftuberculosis that shortens the duration of the treatment, decreases therates of drug resistance and/or allows for complete or nearly completetuberculosis eradication.

It is an object of the present disclosure to provide compounds useful inthe treatment and/or prevention of tuberculosis. Further, it is anobject of the present disclosure to provide compounds that may be usedin combination with current therapeutic agents such as isoniazid toimprove treatment and/or prevention of tuberculosis.

SUMMARY

The present disclosure provides a combination comprising:

(i) a drug against tuberculosis,or a pharmaceutically acceptable salt thereof; and(ii) a compound of Formula II

or a pharmaceutically acceptable salt thereof,whereinR₁ is selected from the group consisting of:

a) C(O)OH,

b) tetrazolyl,

c) CH₂OH,

d) C(O)NR_(6a)R_(6b),e) C(O)NHSO₂R₇,

f) C(O)OR₈, g) NH₂, h) H,

R₂ is selected from the group consisting of:

a) H, b) Cl, F, Br or I, c) CH₂OH,

d) C₁-C₄alkyl, ande) NY₁Y₂,R₃ is selected from the group consisting of:a) 1-naphtyl, 2-naphtyl or 1-naphtyloxy, each independently substitutedwith 0, 1, 2 or 3 substituents selected from the group consisting ofmethyl, fluoro, chloro, bromo, cyano and methoxy,b) phenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro, cyano andtrifluoromethyl,c) aminophenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro andtrifluoromethyld) 2-(3-methyl)phenylmethylene,e) benzothiophene-2-yl,f) H or C₁-C₄-alkyl,g) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy,h) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,i) 2-methyl-1-aza-2-bora-1H-naphth-8-yloxy, andj) 2-methyl-1-aza-2-bora-1H-naphth-8-yl,R₄ is selected from the group consisting of:a) C₁-C₄alkyl substituted by 0, 1, 2, 3 or 4 fluoro;b) C₃-C₆cycloalkyl,c) C₁-C₄alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,d) C₃-C₆cycloalkoxy,e) a 3-, 4-, 5- or 6-membered heterocycle,f) N-methyl 3-indolyl, andh) NR₉R₁₀,R₅ is selected from the group consisting of:

a) H,

b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),c) benzyl,d) thienyl,e) C₁-C₄alkoxy, andf) a 3-, 4-, 5- or 6-membered heterocycle.

There is also provided a combination as described herein for use as amedicament in therapy.

Further, there is provided a combination as described herein for use inthe treatment and/or prevention of tuberculosis.

Further, there is provided the use of a combination as described hereinfor the manufacture of a medicament for the treatment and/or preventionof tuberculosis.

There is also provided a method for treatment and/or prevention oftuberculosis comprising administering to a mammal, such as a human or ananimal, in need thereof an effective amount of a combination asdescribed herein.

The present disclosure also provides a compound of Formula II asdescribed herein for use in the treatment and/or prevention oftuberculosis.

There is also provided a use of a compound of Formula II as describedherein for the manufacture of a medicament for the treatment and/orprevention of tuberculosis.

There is also provided a method for treatment and/or prevention oftuberculosis comprising administering to a mammal, such as a human or ananimal, in need thereof an effective amount of a compound of Formula IIas described herein.

Moreover, there is provided a compound of Formula IIIa and/or IIIb:

wherein A- is selected from:

COO⁻,

orC(O)N⁻SO₂R₇, andwhereinR₂, R₃, R₄, R₅ and R₇ may be as described for Formula II,or a pharmaceutically acceptable salt thereof.

There is also provided a compound of compound of Formula IIIa and/orFormula IIIb for use as a medicament in therapy.

The present disclosure also provides a compound of Formula IV:

or a pharmaceutically acceptable salt thereof. R₂, R₃, R₄, and R₅ may beas described for Formula II. There is also provided a compound ofFormula IV as a medicament in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemical structures of the drugs rifampicin (RIF),pyrazinamide (PZA) and ethambutol (EMB).

FIG. 2 shows the chemical structures of the drugs bedaquiline,ethionamide, delamanide and pretomanid.

FIG. 3 shows compounds of Formula IIIa and Formula IIIb.

FIG. 4 shows compounds of Formula IVa1, IVa2, IVa3 and IVa4.

FIG. 5 a shows an agar plate containing 0.05% DMSO and inoculated with1.959×10⁸ CFU of Mycobacterium tuberculosis and a disk spotted with 5 μlof water placed onto the plate at the time of inoculation. Photo wastaken after 4 weeks of incubation at 37° C. in 5% CO₂.

FIG. 5 b shows an agar plate containing 0.05% DMSO and inoculated with1.959×10⁸ CFU of Mycobacterium tuberculosis and a disk spotted with 5 μlof 0.5 mg/ml INH placed onto the plate at the time of inoculation. Photowas taken after 4 weeks of incubation at 37° C. in 5% CO₂.

FIG. 5 c shows an agar plate containing a DMSO solution of 25 μM(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid and inoculated with 1.959×10⁸ CFU of Mycobacterium tuberculosis anda disk spotted with 5 μl of water placed onto the plate at the time ofinoculation. Photo was taken after 4 weeks of incubation at 37° C. in 5%CO₂.

FIG. 5 d shows an agar plate containing a DMSO solution of 25 μM(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid and inoculated with 1.959×10⁸CFU of Mycobacterium tuberculosis anda disk spotted with 5 μl of 0.5 mg/ml INH placed onto the plate at thetime of inoculation. Photo was taken after 4 weeks of incubation at 37°C. in 5% CO₂.

FIG. 6 shows the ratio of colony forming units of treated/untreatedtuberculosis bacteria upon addition of isoniazid, a combination ofisoniazid and the compound of Example 1 described herein and acombination of isoniazid and the compound of Example 19 as describedherein, respectively.

FIG. 7 shows compounds of Formula Va1, Formula Va2, Formula Va3 andFormula Va4.

FIG. 8 a shows WT Mtb growth in planktonic, aerated cultures.

FIG. 8 b shows WT Mtb plated for CFUs to determine live Mtb.

FIG. 8 c shows a photograph of growth of plated WT Mtb on an agar platewhen INH and the compound of Example 1 were absent.

FIG. 8 d shows a photograph of growth of plated WT Mtb on an agar platefor INH.

FIG. 8 e shows a photograph of growth of plated WT Mtb on an agar platefor the compound of Example 1.

FIG. 8 f shows a photograph of growth of plated WT Mtb on an agar platefor a combination of INH and the compound of Example 1.

FIG. 9 a shows katGFASAA6 Mtb growth in planktonic, aerated cultures.

FIG. 9 b shows katGFASAA6 Mtb plated for CFUs to determine live Mtb.

FIG. 9 c a photograph of shows growth of plated katGFASAA6 Mtb on anagar plate when INH and the compound of Example 1 were absent.

FIG. 9 d shows a photograph of growth of plated katGFASAA6 Mtb on anagar plate for INH.

FIG. 9 e shows a photograph of growth of plated katGFASAA6 Mtb on anagar plate for the compound of Example 1.

FIG. 9 f shows a photograph of growth of plated katGFASAA6 Mtb on anagar plate for a combination of INH and the compound of Example 1.

DETAILED DESCRIPTION

The present disclosure provides a combination comprising:

(i) a drug against tuberculosis,or a pharmaceutically acceptable salt thereof; and(ii) a compound of Formula II

or a pharmaceutically acceptable salt thereof,whereinR₁ is selected from the group consisting of:

a) C(O)OH,

b) tetrazolyl,

c) CH₂OH,

d) C(O)NR_(6a)R_(6b),e) C(O)NHSO₂R₇,

f) C(O)OR₈, g) NH₂, h) H,

R₂ is selected from the group consisting of:

a) H, b) Cl, F, Br or I, c) CH₂OH,

d) C₁-C₄alkyl, ande) NY₁Y₂,R₃ is selected from the group consisting of:a) 1-naphtyl, 2-naphtyl or 1-naphtyloxy, each independently substitutedwith 0, 1, 2 or 3 substituents selected from the group consisting ofmethyl, fluoro, chloro, bromo, cyano and methoxy,b) phenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro, cyano andtrifluoromethyl,c) aminophenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro andtrifluoromethyl,d) 2-(3-methyl)phenylmethylene,e) benzothiophene-2-yl,f) H or C₁-C₄-alkyl,i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, andj) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,R₄ is selected from the group consisting of:a) C₁-C₄alkyl substituted by 0, 1, 2, 3 or 4 fluoro,b) C₃-C₆cycloalkyl,c) C₁-C₄alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,d) C₃-C₆cycloalkoxy,e) a-3-, 4-, 5- or 6-membered heterocycle,f) N-methyl 3-indolyl, andh) NR₉R₁₀,R₅ is selected from the group consisting of:

a) H,

b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),c) benzyl,d) thienyl,e) C₁-C₄alkoxy, andf) a 3-, 4-, 5- or 6-membered heterocycle.

The following definitions shall apply throughout this document unlessstated otherwise.

R_(6a) is selected from the group consisting of H and C₁-C₄alkyl.R_(6b) is selected from the group consisting of H, C₁-C₄alkyl,C₁-C₄alkoxy and isonicotinoylamino.R₇ is SO₂C₁-C₄alkyl or SO₂phenyl.R₈ represents 2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl).R_(9a) represents C₁-C₄alkyl,R_(9b) represents C₁-C₄alkyl,R₁₀ represents C₁-C₄alkyl, orR₉ and R₁₀ together form CH₂(CH₂)_(m)CH₂.Y₁ and Y₂ each independently represents hydrogen, methyl, CH₃S(O)₂ orC(O)CH₃, or Y₁ and Y₂ together form CH₂CH₂CH₂CH₂ or CH₂CH₂CH₂CH₂CH₂.

X is S, SO or SO₂.

m is 1, 2 or 3.

The term “C₁-C₄alkyl” denotes a straight or branched, saturated orunsaturated alkyl group of one to four carbon atoms. Examples of“C₁-C₄alkyl” include, but are not limited to, methyl, ethyl, vinyl,allyl, n-propyl, isopropyl, n-butyl, sec-butyl.iso-butyl and tert-butyl.

The term “C₁-C₄alkoxy” denotes a C₁-C₄alkyl group as described hereinwhich is linked to an oxygen atom. Examples of “C₁-C₄alkoxy” include,but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy andbutoxy.

The term “C₃-C₆cycloalkyl” denotes a saturated or unsaturatednon-aromatic monocyclic ring composed of three, four, five or six carbonatoms. Examples of “C₃-C₆cycloalkyl” include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “C₃-C₆cycloalkoxy” denotes a saturated or unsaturatednon-aromatic monocyclic ring composed of three, four, five or six carbonatoms which is linked to an oxygen atom. Examples of “C₃-C₆cycloalkoxy”include, but are not limited to, cyclopropyloxy, cyclopropxymethylene,cyclobutyloxy, cyclobutyloxymethylene, cyclopentyloxy,cyclopentyloxymethylene, cyclohexyloxyand cyclohexyloxymethylene.

The term “3-membered heterocycle” denotes a 3-membered saturated orunsaturated heterocycle. Examples of a 3-membered saturated heterocycleinclude, but are not limited to, aziridine, oxirane and thiirane.Examples of 3-membered unsaturated heterocycles include, but are notlimited to, azirine, oxirene and thiirene.

The term “4-membered heterocycle” denotes a 4-membered saturated orunsaturated heterocycle. Examples of a 4-membered heterocycle include,but are not limited to, azetidine, oxethane and thietane.

The term “5-membered heterocycle” denotes a 5-membered saturated orunsaturated heterocycle. Examples of a 5-membered heterocycles include,but are not limited to pyrrolidine, tetrahydrofurane, thiolane, pyrrole,furane, thiophene, imidazolidine, pyrazolidine, pxazolidine,isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane,imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole

The term “6-membered heterocycle” denotes a 6-membered saturated orunsaturated heterocycle. Examples of a 6-membered heterocycles include,but are not limited to piperidine, pyridine, piperazine, morpholine, andthiomorpholine.

The drug against tuberculosis is to be understood as a drug thatcounteracts tuberculosis bacteria. The drug against tuberculosis mayreduce, substantially eliminate or eradicate tuberculosis bacteria. Thedrug against tuberculosis may also be denominated an anti-tuberculosisdrug or a drug to treat tuberculosis.

Examples of drugs against tuberculosis that may be used in combinationwith the compounds of Formula II as described herein include first lineanti-tuberculous drugs, second line anti-tuberculous drugs and/or thirdline anti-tuberculous drugs. First line anti-tuberculous drugs may be atleast one of the following: isoniazid, ethambuthol, pyrazinamide,rifampicin, streptomycin. For instance, the drug against tuberculosismay be at least one of the following: isoniazid, ethambuthol,pyrazinamide, rifampicin. In an example, the drug against tuberculosismay be isoniazid optionally in combination with at least one ofethambuthol, pyrazinamide, rifampicin.

Second line anti-tuberculosis drugs may be at least one of thefollowing:

aminoglycosides, such as amikacin or kanamycin,polypeptides such as capreomycin, viomycin, enviomycin,fluoroquinolones such as ciprofloxacin (CIP), levofloxacin, moxifloxacin(MXF);thioamides such as ethionamide, prothionamide,cycloserine,terizidone.

Third line anti-tuberculosis drugs may be at least one of the following:

rifabutin,macrolides such as chlaritromycin (CLLR),linezolid (LZD),thioridazine;arginine,vitamin D,bedaquiline,pretomanid,delamanid.

Examples of drugs against tuberculosis that may be used in combinationwith the compounds of Formula II as described herein include isoniazid,pyrazinamide, pretomanid, delamanid, bedaquiline, streptomycin,levofloxacin, moxifloxacin and ofloxacin, cycloserine, terizidone,thionamide, protionamide and-4-aminosalicylic acid. For instance, thedrug against tuberculosis may be isoniazid and/or 4-aminosalicylic acid.In a further example, the drug against tuberculosis may be isoniazideand/or bedaquiline, optionally in combination with at least one ofethambutol, pyrazinamide, rifampicin.

In addition or as an alternative to the compounds of Formula IIdescribed herein, the compounds described in WO 2014/185853 and/orPCT/EP2015/076578 are provided and incorporated by reference. Thesecompounds may be used in combination with the drug against tuberculosisdescribed herein and/or in the treatment and/or prevention oftuberculosis.

In this document, isonicotinylhydrazide has the chemical structure shownbelow. Isonicotinylhydrazide is also denominated isoniazid (INH). Inthis document, the terms isonicotinylhydrazide, isoniazid and INH areused interchangeably.

In this document, the drugs rifampicin (RIF), pyrazinamide (PZA) and/orethambutol (EMB) are understood to have the chemical structures depictedin FIG. 1 . Further, bedaquiline, ethionamide, delamanide and pretomanidare understood to have the chemical structures depicted in FIG. 2 .

Surprisingly, the inventors of the present disclosure have found thatthe compounds of Formula II described herein are useful in the treatmentand/or prevention of tuberculosis.

The compounds of Formula II may be used separately or in combinationwith a drug against tuberculosis such as INH.

In an example, there is provided a combination as described hereinwherein the drug against tuberculosis is isoniazid.

In a further example, there is provided a combination comprising:

(i) a compound of Formula I

i.e. isonicotinylhydrazide,or a pharmaceutically acceptable salt thereof, and(ii) a compound of Formula II

or a pharmaceutically acceptable salt thereof,whereinR₁ is selected from the group consisting of:

a) C(O)OH,

b) tetrazolyl,

c) CH₂OH,

d) C(O)NR_(6a)R_(6b),e) C(O)NHSO₂R₇,

f) C(O)OR₈, g) NH₂, h) H,

R₂ is selected from the group consisting of:

a) H, b) Cl, F, Br or I, and c) CH₂OH,

R₃ is selected from the group consisting of:a) 1-naphtyl, 2-naphtyl or 1-naphtyloxy, each independently substitutedwith 0, 1, 2 or 3 substituents selected from the group consisting ofmethyl, fluoro, chloro, bromo, cyano and methoxy,b) phenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro, cyano andtrifluoromethyl,c) aminophenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro andtrifluoromethyld) 2-(3-methyl)phenylmethylene,e) benzothiophene-2-yl,f) H or C₁-C₄-alkyl,i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, andj) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,R₄ is selected from the group consisting of:a) C₁-C₄alkyl substituted by 0, 1, 2, 3 or 4 fluoro;b) C₃-C₆cycloalkyl,c) C₁-C₄alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,d) C₃-C₆cycloalkoxy,e) 2-thienyl,f) N-methyl 3-indolyl, andh) NR₉R₁₀,R₅ is selected from the group consisting of:

a) H,

b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),c) benzyl,d) thienyl,e) C₁-C₄alkoxy, andf) 1-triazolyl.

Further values of wherein R₁, R₂, R₃, R₄, R₅, m and X will now follow.It will be appreciated that these values may be applied to any compoundof Formula II of the present disclosure.

R₁ may be C(O)OH or tetrazolyl. For instance, R₁ may be C(O)OH.

R₂ may be H.

R₃ may be selected from the group consisting of:a) 1-naphtyl, 2-naphtyl or 1-naphtyloxy, each independently substitutedwith 0, 1, 2 or 3 substituents selected from the group consisting ofmethyl, fluoro, chloro, cyano and methoxy, andb) phenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro, cyano andtrifluoromethyl.

Further, R₃ may be selected from selected from the group consisting of:1-naphtyl, 2-naphtyl, 4-methyl-1-naphtyl, 4-fluoro-1-naphtyl,4-bromo-1-naphtyl, 4-methoxy-1-naphtyl, 2-methoxy-1-naphtyl,2-methoxy-1-naphtyl, 1-naphtyloxy, 3-methylphenyl, 2,3-dimethylphenyl,2-fluoro-5-methylphenyl, 2,3-dichlorophenyl,2-(3-methyl)phenylmethylene; 2,3-xylylamine, 3-trifluoromethylphenyl andbenzothiophene-2-yl.

In still a further example, R₃ may be selected from the group consistingof:

a) 1-naphtyl, 2-naphtyl or 1-naphtyloxy, each independently substitutedwith 0, 1, 2 or 3 substituents selected from the group consisting ofmethyl, fluoro, chloro, cyano and methoxy. For instance, R₃ may be1-naphtyl.R₄ may be C₂-C₆cycloalkyl. For instance, R₄ may be cyclopropyl.

R₅ may be H.

X may be S or SO. For instance, X may be S. In a further example, X maybe SO. In still a further example, X may be SO₂.

The compound of Formula II may exist as Formula IIa or Formula IIb,wherein R₁, R₂, R₃, R₄, R₅ and X may have the values described herein.

Further, the compound of Formula IIa may exist as cis stereoisomersFormula IIa1 and Formula IIa2 or as trans stereosiomers of Formula IIa3or Formula IIa4. R₁, R₂, R₃, R₄, R₅ and X may have values as describedherein.

When R₅ is hydrogen the compound of Formula IIa may be depicted as acompound of Formula IIa5, Formula IIa51 or Formula IIa52. The compoundof Formula IIa5 may be a racemate comprising the compounds of FormulaIIa51 or Formula IIa52. For these compounds, R₁, R₂, R₃, R₄ and X mayhave values described herein.

As described herein, X may be S, SO or SO₂ for the compounds of thepresent disclosure. Accordingly, when X is S the bicyclic ring structurecontains a sulfide. When X is SO the bicyclic ring structure contains asulphoxide. When X is SO₂ the bicyclic ring structure contains asulphone.

By way of example, the compound of Formula IIa51 may exist as a compoundof Formula IIa511, Formula IIa512 or Formula IIa513. R₁, R₂, R₃ and R₄,may have values as described herein. It will be appreciated that X is Sin the compound of Formula IIa511, X is SO in the compound of FormulaIIa512 and X is SO₂ in the compound of Formula IIa513. Further, albeitsulphoxides generally are depicted with a double bond between the sulfuratom and the oxygen atom such as in the compound of Formula IIa512 it isunderstood that the sulfur atom of the sulphoxide is a chiral center,and consequently may exhibit R or S stereochemistry at the sulphoxidechiral center.

When R₁ is an acidic group AH such as C(O)OH, tetrazole or C(O)NHSO₂R₇the compound of Formula TT may form a salt with an antituberculosis drugsuch as isoniazide thereby providing a salt of Formula IIIa or FormulaIIIb. For these compounds, A⁻, R₂, R₃, R₄, R₅, R₇ and X may have valuesas described herein. It will be appreciated that the isoniazide ofFormulas IIIa or Formula IIIb may be replaced with another drug againsttuberculosis such as bedaquiline.

The present disclosure provides a salt of Formula IIIa and/or FormulaIIIb. Further, it will be appreciated that the salt of Formula IIIb mayexist as stereoisomers, and the present disclosure provides all suchstereoisomers. The salt of Formula IIIa and/or Formula IIIb may be usedin combination with a drug against tuberculosis such as isoniazid orbedaquiline. Alternatively, it may be used as such, optionally togetherwith a pharmaceutical excipient diluent and/or carrier. For instance,the salt of Formula IIIa and/or Formula IIIb may be used in preventionof tuberculosis. In this document, the salts of Formula IIIa and/orFormula IIIb are also denominated compounds of Formula IIIa and/orFormula IIIb.

Further, the present disclosure provides a compound of Formula IV, or apharmaceutically acceptable salt thereof. R₂, R₃, R₄, R₅ and X may havevalues as described herein. The compound of Formula IV may be providedby reacting isoniazide with a compound of Formula II, wherein R₁ isC(O)OH), of the present disclosure. In this reaction, R₁ may betransformed from C(O)OH into C(O)Cl prior to reaction with the compoundof Formula IV. The compound of Formula IV may be provided in combinationwith isoniazid. Alternatively, it may be used as such in, optionally incombination with a pharmaceutical excipient, diluent and/or carrier.

The compound of Formula IV may exist as a compound of Formula IVa or asa compound of Formula IVb. R₂, R₃, R₄, R₅ and X may have values asdescribed herein. For instance, R₅ may be hydrogen and X may be S, SO orSO₂.

The compound of Formula IVa may exist as cis and trans stereoisomers.The present disclosure encompasses all these compounds which aredenominated compounds of Formula IVa1, IVa2, IVa3 and IVa4, the chemicalstructures of which are shown in FIG. 5 .

As an example of a compound of Formula IVa the present disclosureprovides{7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde.

Further, it will be appreciated that instead of the isoniazide moiety ofFormula IV another drug against tuberculosis may be used.

The present disclosure further provides a combination comprising:

(i) a composition comprising or consisting of a drug againsttuberculosis such as isonicotinylhydrazide or bedaquiline, or apharmaceutically acceptable salt thereof, and(ii) a composition comprising or consisting of a compound of Formula IIas described herein, or a pharmaceutically acceptable salt thereof.

Further, the combination described herein may be provided as a kit ofparts. Thus, there is provided a kit of parts comprising:

(i) a composition comprising or consisting of a drug againsttuberculosis such as isonicotinylhydrazide or bedaquiline, or apharmaceutically acceptable salt thereof, and(ii) a composition comprising or consisting of a compound of Formula IIas described herein, or a pharmaceutically acceptable salt thereof.

The combination described herein may be provided as a single compositioncomprising

(i) a drug against tuberculosis such as isonicotinylhydrazide orbedaquiline, or a pharmaceutically acceptable salt thereof, and(ii) a compound of Formula II as described herein, or a pharmaceuticallyacceptable salt thereof.

For instance, the single composition may be provided as a tablet,lozenge or sirup.

The combination described herein such as the kit of parts may furthercomprise instructions for use. For instance, the instructions for usemay be instructions for separate, sequential or simultaneous use of the(i) composition comprising or consisting of a drug against tuberculosissuch as isonicotinylhydrazide, or a pharmaceutically acceptable saltthereof and the (ii) composition comprising or consisting of a compoundof Formula II as described herein, or a pharmaceutically acceptable saltthereof.

The drug against tuberculosis described herein may be selected from atleast one of the following: isoniazid, rifampicin, pyrazinamide,ethambutol, pretomanid, delamanid, bedaquiline, streptomycin,levofloxacin, moxifloxacin and ofloxacin, cycloserine, terizidone,thionamide, protionamide, clofazimine and-4-aminosalicylic acid. Forinstance, the drug against tuberculosis described herein may be selectedfrom at least one of the following: isonicotinylhydrazide, bedaquiline,ethionamide, pretomanid, 4-aminosalisalicylic acid. In an example, thedrug against tuberculosis may be isonicotinylhydrazide and/orbedaquiline, optionally in combination with at least one of ethambuthol,pyrazinamide, rifampicin. In a further example, the drug againsttuberculosis may be as described elsewhere in this document. Thecombination of the present disclosure may further comprise a drugselected from the group consisting of rifampicin, pyrazinamide,ethambutol and 4-aminosalisalicylic acid. In particular, the combinationof the present disclosure may further comprise a drug selected from thegroup consisting of rifampicin, pyrazinamide and ethambutol.

In an example, the drug against tuberculosis described herein maycomprise or consist of isonicotinylhydrazide, rifampicin, pyrazinamideand ethambutol.

Further, in an example the drug against tuberculosis described hereindoes not solely consist of rifampicin, pyrazinamide or ethambutol. Thus,when rifampicin, pyrazinamide or ethambutol are used they may or shouldbe used in combination with another drug against tuberculosis.

The combination described herein may comprise a compound of Formula IIselected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde-   (3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic    acid-   (2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   2-{2-[1-(Hydroxymethyl) propylamino]ethylamino}butyl    7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate-   {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde-   7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In a further example, the combination described herein may comprise acompound of Formula II selected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde-   (3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic    acid-   (2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   2-{2-[1-(Hydroxymethyl) propylamino]ethylamino}butyl    7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate-   {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde-   7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In still a further example, the combination described herein maycomprise a compound of Formula II selected from at least one of:

-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In a further example, the combination described herein may comprise acompound of Formula II selected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde-   (3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic    acid-   (2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In a further example, the combination described herein may comprise acompound of Formula II selected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde-   (3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone-   (2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic    acid-   (2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In a further example, the present disclosure provides a compound ofFormula II, which may be part of and/or used in the combinationdescribed herein, said compound being selected from at least one of:

-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   2-{2-[1-(Hydroxymethyl) propylamino]ethylamino}butyl    7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate-   {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde-   7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds. There is also provided a compound of Formula II as    described in this paragraph as such.

In a further example, the combination described herein may comprise acompound of Formula II selected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   2-{2-[1-(Hydroxymethyl) propylamino]ethylamino}butyl    7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate-   {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In a further example, the combination described herein may comprise acompound of Formula II selected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   2-{2-[1-(Hydroxymethyl) propylamino]ethylamino}butyl    7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate-   {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde-   (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic    acid-   (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide    7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

The combination described herein may comprise a compound of Formula IIselected from at least one of:

-   (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic    acid-   7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic    acid,-   (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic    or a pharmaceutically acceptable salt of any of the foregoing    compounds.

In an example, the combination described herein may comprise thecompound(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid or a pharmaceutically acceptable salt thereof. In a furtherexample, the combination described herein may comprise the compound7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylicacid or a pharmaceutically acceptable salt thereof. In still a furtherexample, the combination described herein may comprise the compound(3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylicor a pharmaceutically acceptable salt thereof.

There is also provided a combination as described herein for use as amedicament.

Further, there is provided a combination as described herein for use inthe treatment and/or prevention of tuberculosis.

There is also provided the use of a combination as described herein forthe manufacture of a medicament for the treatment and/or prevention oftuberculosis.

There is also provided a method for treatment and/or prevention oftuberculosis comprising administering to a mammal, such as a human or ananimal, in need thereof an effective amount of a combination asdescribed herein. In this document, a mammal may be a human and/or ananimal.

The tuberculosis described in this document may involve Mycobacteriumtuberculosis (Mtb). Additionally or alternatively, the tuberculosis mayinvolve one or more tuberculosis causing bacteria selected from thegroup consisting of M. bovis, M. africanum, M. canetti and/or M.microti. The tuberculosis may be active, latent, drug-sensitive and/ordrug-resistant tuberculosis. Further, the tuberculosis may be one ormore selected from the group consisting of pulmonary tuberculosis,military tuberculosis, laryngeal tuberculosis, extrapulmonarytuberculosis, tuberculosis peritonitis, tuberculosis pericarditis,osteal tuberculosis, renal tuberculosis, adrenal tuberculosis andtuberculosis meningitis.

The treatment described herein, such as a treatment using thecombination of the present disclosure, may be curative treatmentinvolving tuberculosis eradication or substantial tuberculosiseradication. In this document, the term eradication intends completeremoval of tuberculosis bacteria or clinical cure where the bacteria areno longer detectable and the patient no longer has symptoms. Thesemeasures of eradication or clinical cure may be determined by sputumsampling and sputum smear and culture.

The prevention described herein, such as prevention using a compound ofFormula II described herein, may involve preventing tuberculosisbacteria from multiplying and/or growing. The prevention is believed tooccur by inhibiting lipid synthesis (in particular, but not limited to,in response to environmental changes) and altering the redox state ofthe bacteria.

As used herein, drug-resistant tuberculosis is intended to meanreduction in the effectiveness of a drug such as an antibiotic in thetreatment of tuberculosis. The tuberculosis bacteria will then no longerbe affected and/or killed by the drug or affected to a very limitedextent. The drug-resistant tuberculosis may be at least one of thefollowing: isoniazid resistant tuberculosis, multi-drug resistanttuberculosis, extensively resistant tuberculosis, totally resistanttuberculosis. Isoniazid resistant tuberculosis involves tuberculosisbacteria that are resistant to treatment with isoniazid. Multi-drugresistant tuberculosis involves tuberculosis bacteria that are resistantto treatment with at least two first line anti-tuberculosis drugs suchas isoniazid and rifampicin. Extensively resistant tuberculosis involvestuberculosis bacteria that are resistant to at least rifampicin andisoniazid, to any member of quinolone broad-spectrum antibiotics and/orsecond line anti-tuberculosis drugs such as kanamycin, capreomyucin,amikacin.

While not wishing to be bound by any specific theory, it is believedthat the compounds of Formula II of the present disclosure affect thetuberculosis bacteria by inhibiting lipid synthesis (in particular, butnot limited to, in response to environmental changes) and altering theredox state of the bacteria. These direct effects lead to inhibition ofthe bacteria's ability to tolerate drugs against tuberculosis such asINH, tolerate low pH, tolerate reactive nitrogen and oxygen species, andform biofilms. The compounds of Formula II also inhibit growth in somestandard media conditions, inhibit the selection for INH resistantmutants due to katG mutation and, therefore, decrease and/or inhibit therate of INH resistance. Further, the compounds of Formula II of thepresent disclosure appear to sensitize resistant tuberculosis bacteriato treatment with a drug against tuberculosis as described herein, suchas INH.

Thus, there is provided a compound of Formula II as described herein foruse as a tuberculosis bacteria tolerance inhibitor. There is alsoprovided the use of a compound of Formula II for the manufacture of amedicament for tuberculosis bacteria tolerance inhibition. There is alsoprovided a method for tuberculosis bacteria tolerance inhibitioncomprising administering to a mammal, such as a human or an animal, aneffective amount of a compound of Formula II as described herein. Thereis also provided a use of a compound of Formula II as described hereinas a tuberculosis bacteria tolerance inhibitor. The tuberculosis may beas described herein.

Thus, there is provided a compound of Formula II as described herein foruse in sensitizing tuberculosis bacteria to treatment with a drugagainst tuberculosis. There is also provided the use of a compound ofFormula II as described herein for the manufacture of a medicament foruse in sensitizing tuberculosis bacteria to treatment with a drugagainst tuberculosis. There is also provided a method for sensitizingtuberculosis bacteria to treatment with a drug against tuberculosiscomprising administering to a mammal, such as a human or an animal, aneffective amount of a compound of Formula II as described herein. Thereis also provided a use of a compound of Formula II as described hereinto sensitize tuberculosis bacteria to treatment with a drug againsttuberculosis. The tuberculosis and/or the drug against tuberculosis maybe as described herein.

Thus, there is provided a compound of Formula II as described herein toimprove the efficacy of a drug against tuberculosis. There is alsoprovided the use of a compound of Formula II as described herein for themanufacture of a medicament to improve the efficacy of a drug againsttuberculosis. There is also provided a method for sensitizingtuberculosis bacteria to treatment with a drug against tuberculosiscomprising administering to a mammal, such as a human or an animal, aneffective amount of a compound of Formula II as described herein toimprove the efficacy of a drug against tuberculosis. There is alsoprovided a use of a compound of Formula II as described herein toimprove the efficacy of a drug against tuberculosis. The tuberculosisand/or the drug against tuberculosis may be as described herein.

A compound of Formula II as described herein is considered to havebiofilm inhibition activity if the biofilm inhibition affects theformation of biofilm to an extent of at least 25%, such as 50%, 75% or100% when used at a molar concentration within the range of from about25 micromolar to about 100 micromolar such as about 25 micromolar, 50micromolar or 100 micromolar. Additionally or alternatively, thecompounds Formula II are considered to have biofilm inhibitory activityif they exhibit full biofilm inhibition as shown in Table 2 herein.

The present disclosure provides a compound of Formula II as describedherein for use in the treatment and/or prevention of tuberculosis. Thereis also provided a use of a compound of Formula II as described hereinfor the manufacture of a medicament for the treatment and/or preventionof tuberculosis. Further, there is provided a method for treatmentand/or prevention of tuberculosis comprising administering to a mammal,such as a human or an animal, an affective amount of a compound ofFormula II as described herein.

There is also provided a compound of Formula IIIa and/or Formula IIIb asdescribed herein for use as a medicament in therapy.

There is also provided a compound of Formula IV as described herein foruse as a medicament in therapy. The compound of Formula IV may be acompound of Formula IVa, IVb, IVa1, IVa2, IVa3 or IVa4 as describedherein.

The present disclosure provides a compound of Formula IIIa and/orFormula IIIb as described herein for use in the treatment and/orprevention of tuberculosis. There is also provided a use of a compoundof Formula IIIa and/or Formula IIIb a as described herein for themanufacture of a medicament for the treatment and/or prevention oftuberculosis.

Further, there is provided a method for treatment and/or prevention oftuberculosis comprising administering to a mammal, such as a human or ananimal, an affective amount of a compound of Formula IIIa and/or FormulaIIIb as described herein.

The present disclosure provides a compound of Formula IV as describedherein for use in the treatment and/or prevention of tuberculosis. Thereis also provided a use of a compound of Formula IV as described hereinfor the manufacture of a medicament for the treatment and/or preventionof tuberculosis. Further, there is provided a method for treatmentand/or prevention of tuberculosis comprising administering to a mammal,such as a human or an animal, an affective amount of a compound ofFormula IV as described herein.

Salts

The compounds of the present disclosure may be provided as apharmaceutically acceptable salt. A suitable pharmaceutically acceptablesalt of a compound of the present disclosure may be, for example, abase-addition salt of a compound of the present disclosure which issufficiently acidic, for example, a metal salt, for example, lithium,sodium, potassium, calcium, magnesium, zinc or aluminum, an ammoniumsalt, a salt with an organic base which affords a physiologicallyacceptable cation, which includes quartenery ammonium hydroxides, forexample methylamine, ethylamine, diethylamine, trimethylamine,tert-butylamine, triethylamine, dibenzylamine, N,N-dibenzylethylamine,cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyldiethylamine, (IR, 2S)-2-hydroxyinden-I-amine, morpholine,N-methylpiperidine, N-ethylpiperidine, imidazole, piperazine,methylpiperazine, adamantylamine, choline hydroxide, tetrabutylammoniumhydroxide, tris-(hydroxymethyl)methylamine hydroxide, L-arginine,N-methyl D-glucamine, lysine or arginine. In an example, there isprovided an imidazole salt of the compounds of the present disclosure.

Solvates or Hydrates

Certain compounds of the present disclosure may exist as solvates orhydrates. It is to be understood that the present disclosure encompassesall such solvates or hydrates. Compounds of the present disclosure mayalso contain unnatural proportions of atomic isotopes at one or more ofthe atoms that constitute such compounds. For example, the compounds maybe radiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.

Co-Crystals

In a salt, proton transfer may occur between the active pharmaceuticalingredient and the counter ion of the salt. However, in some cases thereis no or only partial proton transfer and the solid is therefore not atrue salt. It is accepted that the proton transfer is in fact acontinuum, and can change with temperature, and therefore the point atwhich a salt is better described as a “co-crystal” may be subjective.The term “co-crystal” as used herein refers to multicomponent system inwhich there exists a host molecule or molecules (active pharmaceuticalingredient) and a guest (or co-former) molecule or molecules. The guestor co-former molecule is defined as existing as a solid at roomtemperature in order to distinguish the co-crystal from solvates.However, a co-crystal may itself form solvates. In a co-crystal there isgenerally predominance for interaction through non-ionic forces, such ashydrogen bonding.

Polymorphs

Compounds of the present disclosure may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline. Thus, it is tobe understood that all polymorphs, such as mixtures of differentpolymorphs, are included within the scope of the claimed compounds.

Prodruqs

In addition, compounds of the present disclosure may be administered inthe form of a prodrug. A prodrug is a compound which may have little orno pharmacological activity itself, but when such compound isadministered into or onto the body of a patient, it is converted into acompound of Formula II.

Methods of Preparation

Compounds of the present disclosure may be prepared as described in WO2014/185853. The compounds may also be prepared as described forstructurally related compounds. The reactions may be carried out as instandard procedures or as described in the experimental section of thisdocument. The sulfide of the compounds of Formula II may be oxidizedwith the aid of meta-chloroperoxybenzoic acid (mCPBA) to sulphoxide andsulphone, respectively. Additionally or alternatively, the compounds maybe prepared as depicted in Schemes 1 to 10 as depicted below.

INTERMEDIATES

The present disclosure provides compounds which may be used asintermediates in the synthesis of compounds of Formula II describedherein. For instance, the intermediates may be at least one of thefollowing compounds:

-   Benzyl (4R)-2-(cyclopropylmethyl)Δ²-1,3-thiazoline-4-carboxylate,-   5-{1-Hydroxy-2-[m-(trifluoromethyl)phenyl]ethylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione,-   Benzyl    (3R)-7-cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylate,-   Methyl    (3R)-7-cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylate.    These intermediates may be used in the synthesis of compounds of    Formula II wherein R₃ is meta-trifluoromethyl, i.e. compounds having    the following chemical structure:

Derivatives of 4-aminosalicylic Acid

4-aminosalicylic acid, commonly known as PAS, is an antibiotic used totreat tuberculosis.

The present disclosure provides a combination comprising:

(i) 4-aminosalicylic acid, i.e.

or a pharmaceutically acceptable salt thereof, and(ii) a compound of Formula II as described herein, wherein R₁, R₂, R₃,R₄, R₅ and X may have values as described in this document, or apharmaceutically acceptable salt thereof.

4-aminosalicylic acid may form a covalent bond with the R₁ group of thecompounds of Formula II disclosed herein resulting in a compound ofFormula V:

whereinR₁₁ is selected from:

R₂, R₃, R₄, R₅ and X may have values as described in this document, or apharmaceutically acceptable salt thereof.

The compound of Formula V may exist as a compound of Formula Va andFormula Vb, respectively:

wherein R₂, R₃, R₄, R₅, R₁₁ and X may have values as described in thisdocument, or a pharmaceutically acceptable salt thereof.

The compound of Formula Va may exist as cis and trans stereoisomers. Thepresent disclosure encompasses all these compounds which are denominatedcompounds of Formula Va1, Va2, Va3 and Va4, the chemical structures ofwhich are shown in FIG. 8 .

Further, there is provided a compound of Formula V as described hereinfor use as a medicament in therapy.

There is also provided a compound of Formula V as described herein foruse in the treatment and/or prevention of tuberculosis. There is alsoprovided the use of a compound of Formula V as described herein for themanufacture of a medicament for the treatment and/or prevention oftuberculosis. There is also provided a method for the treatment and/orprevention of tuberculosis comprising administering to a mammal, such asa human or an animal, an effective amount of a compound of Formula V asdescribed herein. The tuberculosis may be as described in this document.

REFERENCES

-   1. Org. Biomol. Chem., 2005, 3, 3886-3892, Åberg, Veronica et al.-   2. Bioorganic & Medicinal Chemistry Letters (2008), 18(12),    3536-3540, Åberg, Veronica et al.-   3. Journal of Medicinal Chemistry (2010), 53(15), 5690-5695,    Chorell, Erik et al-   4. Tetrahedron Letters (2007), 48(26), 4543-4546, Pemberton, Nils et    al-   5. Bioorganic & Medicinal Chemistry (2012), 20(9), 3128-3142,    Chorell, Erik et al.-   6. Organic & Biomolecular Chemistry (2005), 3(15), 2817-2823,    Aaberg, Veronica et al-   7. WO2014/185853 A1.-   8. Journal of Organic Chemistry (2007), 72(13), 4917-4924, Chorell,    Erik et al.-   9. Comb. Chem. 2002, 4, 630-639, Emtenäs, Hans et al.-   10. J. Med. Chem. 2016, 59, 2094-2108, James A. D. Good et al.-   11. Cell Chemical Biology 23, 404-414, James A. D. Good et al.-   12. PCT/EP2015/076578

The disclosure is further illustrated by the following non-limitativeExamples

EXAMPLES

In this document, unless otherwise stated, the naming and the drawing ofthe chemical compounds and radicals have been made using the programChem Doodle version 7.0.1 or version 7.0.2. If the name and drawing areinconsistent, the chemical structure shall be considered to be correct.

Abbreviations

-   ANOVA Analysis of variance-   aq aqueous-   BOC tert-butyloxycarbonyl-   BSA Bovine Serum Albumine-   CFU Colony Forming Unit-   CPME Cyclopentyl methyl ether-   DCC Dicyclohexyl carbodiimide-   DMAP Dimethyl aminopyridine-   DMF Dimethyl formamide-   DCM Dichloromethane-   EMB Ethambutol-   FAB Fast Atom Bombardment-   HRMS High Resolution Mass Spectrosopy-   INH Isoniazide or isonicotinylhydrazide-   IUPAC International Union of Pure and Applied Chemistry-   OADC Middlebrook Oleic Albumin Dextrose Catalase Growth Supplement-   KatG catalase-peroxidase-   MeCN Acetonitrile-   MIC minimum inhibitory concentration-   MicroM micromolar-   μM micromolar-   Mtb Mycobacterium tuberculosis-   MW Microwave heating-   MS Mass Spectroscopy-   NMR Nuclear Magnetic Resonance-   ND none detected-   nm nanometer-   OD optical density-   λ wavelength-   ODλ₆₀₀ optical density at 600 nm-   PBS Phosphate-Buffered Saline buffer-   PZA Pyrazinamide-   RIF Rifampicin or Rifampin-   RT room temperature-   rt room temperature-   sat saturated-   TB tuberculosis-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TWEEN 80 Polyoxyethylenesorbitan monooleate-   WT Wild Type

CHEMISTRY General

¹H NMR spectra were recorded on a 400 or 600 MHz spectrometer at 298 Kand calibrated by using the residual peak of the solvent as the internalstandard (CDCl₃: δ_(H)=7.26 ppm; δ_(c)=77.16 ppm; DMSO-d₆: δ_(H)=2.50ppm; δ_(c)=39.52 ppm). The purity of all final compounds was ≥95% byLC-MS.

Examples 1-54

The compounds of Examples 1-54 were prepared in accordance with or inanalogy with references 1-11 as described herein or as described in thisdocument. ¹H NMR data are provided for new compounds 36-50.Additionally, NMR data are provided for examples 1, and 27. Table 1shows data for Examples 1-54.

By way of example, the compound of Example 1 was prepared as follows.

Example 1(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicAcid

Cyclopropylacetonitrile was reacted with ethanol and acetyl chloride togenerate 2-cyclopropyl-1-ethoxy-1-ethanimine that was reacted with(R)-cysteine methyl ester hydrochloride and Et₃N in CH₂Cl₂ without anyworkup to form Methyl2-(cyclopropylmethyl)Δ²-1,3-thiazoline-4-carboxylate. (1-Naphthyl)aceticacid activated with DCC and DMAP was reacted with2,2-Dimethyl-1,3-dioxane-4,6-dione in DCM to give5-[1-Hydroxy-2-(1-naphthyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione.

These two building blocks were allowed to react with TFA at elevatedtemperature to give Benzyl(3R)-7-cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylate.Hydrolysis with LiOH in THF or LiBr and Et3N in wet (2%) acetonitrilegave(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid (Scheme 1). NMR and MS data are provided in Table 1.

TABLE 1 Ex- ample Num- Chemical Structure IUPAC name ber ¹H-NMR and andHRMS data 1

3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4- oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR: δ 7.93-7.99 (m, 1H), 7.83-7.92 (m, 2H),7.46-7.56 (m, 3H), 7.36 (d, J 6.95 Hz, 1H), 5.16 (s, 1H), 4.92-4.97 (m,1H), 4.45 (d, J 17.29 Hz, 1H), 4.34 (d, J 17.29 Hz, 1H), 3.47-3.56 (m,2H), 1.62-1.69 (m, 1H), 0.78-0.96 (m, 2H), 0.56-0.73 (m, 2H). HRMS(FAB+) calcd for (M + 1) C₂₂H₂₀NO₃S: 378.1164. Observed: 378.1163. 2

(3R)-7-Cyclopropyl-4-oxo-6-{(7- thiabicyclo[4.3.0]nona- 1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3- indancarboxylic acid ¹H NMR (400 MHz,DMSO-d6): δ = d 0.53-0.73 (m, 2H), 0.81-0.97 (m, 2H), 1.56-1.67 (m, 1H),3.50 (dd J1 = 1.81 Hz, J2 = 11.93 Hz, 1H), 3.78 (dd J1 = 9.12 Hz, J2 =11.91 Hz, 1H), 4.15-4.30 (m, 2H), 5.37 (dd J1 = 1.78 Hz, J2 = 9.10 Hz,1H), 5.61 (s, 1H), 7.35-7.43 (m, 2H), 7.47 (s, 1H), 7.71-7.77 (m, 1H),7.97-8.04 (m, 1H). HRMS (electrospray ionization) calcd for [M + Li]C₂₀H₁₆NO₃S₂ 382.0572. Observed 382.0578 3

(3R)-7-Cyclopropyl- 6-[(4-fluoro-1- naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid 4

(3R)-7-Cyclopropyl-6- [(4-methyl-1- naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid 5

(3S)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4- oxo-1-thia-3a-aza-3-indancarboxylic acid 6

5-Cyclopropyl-4-[(1- naphthyl)methyl]- 2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9- carboxylic acid 7

(3R)-7-Cyclopropyl-6-[(1- naphthyloxy)methyl]-4- oxo-1-thia-3a-aza-3-indancarboxylic acid 8

(3R)-7-Cyclopropyl-6- [(2-fluoro-5- methyl-phenyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid 9

(3R)-7-Cyclopropyl-4- oxo-6-[(2,3- xylyl)methyl]- 1-thia-3a-aza-3-indancarboxylic acid 10

(3R)-7-Methyl-6- [(1-naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid 11

(N-Methylmethoxyamino){(3R)-7- cyclopropyl-6- [(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3- indanyl}formaldehyde 12

(3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-3- (1H-1,2,3,4-tetrazol-5-yl)-1-thia- 3a-aza-4-indanone 13

5-Cyclopropyl-4- [(1-naphthyl)methyl]- 2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9- carboxylic acid 14

5-Cyclopropyl-4- [(1-naphthyl)methyl]-2- oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9- carboxylic acid 15

(3R)-7-Cyclopropyl-6-[(2- naphthyl)methyl]-4-oxo- 1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (DMSO, 400 MHz) d = 8.13-8.10 (m, 1H),7.95-7.92 (m, 1H), 7.67-7.64 (m, 2H), 7.54 (s, 1H), 7.37-7.31 (m, 2H),5.25 (d, 1H, J = 8.8 Hz), 5.23 (s, 1H), 4.46 (d, 1H, J = 17.6 Hz), 4.37(d, 1H, J = 17.6 Hz), 3.72 (dd, 1H, J = 9.2, 11.6 Hz), 3.51 (d, 1H, J =11.6 Hz), 1.74- 1.67 (m, 1H), 0.93-0.86 (m, 2H), 0.66-0.60 (m, 2H) ppm.16

(3R)-7-Cyclopropyl-3- (hydroxymethyl)- 6-[(1-naphthyl)methyl]-1-thia-3a-aza-4- indanone 17

(3R)-6-[(1-Naphthyl)methyl]- 4-oxo-7-(2-thienyl)-1-thia- 3a-aza-3-indancarboxylic acid 18

5-Cyclopropyl-4-[(1- naphthyl)methyl]- 2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1- azabicyclo[4.3.0]nona- 3,5,8-triene-9- carboxylic acid 19

8-Benzyl-5-cyclopropyl-4-[(1- naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9- carboxylic acid 20

(3R)-7-Cyclopropyl-6-[(2,3- dichlorophenyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid 21

(3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4-oxo- 1-thia-3a-aza-3-indancarboxamide 22

{(3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4-oxo- 1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)- formaldehyde 23

(3R)-7-Isopropyl-6-[(1- naphthyl)methyl]-4-oxo- 1-thia-3a-aza-3-indancarboxylic acid 24

(3R)-7-Cyclopropyl-6- methyl-4-oxo-1- thia-3a-aza-3- indancarboxylicacid 25

(3R)-6-[(p-Chlorophenyl)methyl]-7- cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid 26

{(3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4-oxo- 1-thia-3a-aza-3-indanyl}(methylsulfonylamino)- formaldehyde 27

(3R)-7-Cyclopropyl-4-oxo-6-[(m- tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, DMSO-d6): δ = 7.23-7.19 (m, 1H),7.06-7.00 (m, 3H), 5.73 (s, 1H), 5.36 (dd, 1H, J = 1.6, 9.2 Hz), 3.93(ABq, 2H, J = 18.2 Hz), 3.77 (dd, 1H, J = 9.2 Hz, 12 Hz), 3.50 (dd, 1H,J = 1.6 Hz, 11.6 Hz), 2.28 (s, 3H), 1.46-1.39 (m, 1H), 0.95-0.82 (m,2H), 0.65- 0.60 (m, 1H), 0.59-0.49 (m, 1H) ppm. 28

(3R)-7-Isopropyl-4-oxo-6-[2-(m- tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic acid 29

7-(1-Methyl-1H- indol-3-yl)-6-[(1- naphthyloxy)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid 30

(3R)-6-[(4-Bromo- 1-naphthyl)methyl]- 7-cyclopropyl-4-oxo-1-thia-3a-aza-3- indancarboxylic acid 31

7-Cyclopropyl-6- [(1-naphthyl)methyl]- 1-thia-3a-aza-4-indanone 32

(3R)-7-Cyclopropyl-5- (hydroxymethyl)- 6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a- aza-3-indancarboxylic acid 33

(3S)-3-Amino-7- cyclopropyl-6-[(1- naphthyl)methyl]- 1-thia-3a-aza-4-indanone 34

(2R,3R)-7-Cyclopropyl-6-[(1- naphthyl)methyl]-4- oxo-2-phenyl-1-thia-3a-aza-3- indancarboxylic acid 35

(2S,3R)-7-Cyclopropyl-2- methoxy-6- [(1-naphthyl)methyl]-4-oxo-1-thia-3a- aza-3-indancarboxylic acid 36

7-Cyclopropyl-4-oxo-6-{[m- (trifluoromethyl)phenyl]- methyl}-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, DMSO-d6): δ = 13.37 (brs, 1H), 7.65-7.52 (m, 4H), 5.71 (s, 1H), 5.39 (dd, J = 1.8, 9.1 Hz, 1H),4.16-4.04 (m, 2H), 3.78 (dd, J = 9.2, 11.9 Hz, 1H), 3.50 (dd, J = 1.8,11.9 Hz, 1H), 1.45- 1.36 (m, 1H), 0.95-0.83 (m, 2H), 0.68-0.59 (m, 1H),0.57-0.48 (m, 1H) ppm. HRMS (ESI+) (m/z): [M + H]+ calcd. forC19H17F3NO3S, 396.0876; found, 396.0869 37

2-{2-[1- (Hydroxymethyl)propylamino]- ethylamino} butyl7-cyclopropyl-6-[(1- naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylate ¹H NMR (400 MHz, DMSO-d6): δ = 7.78 (d, J = 8.0 Hz,1H), 7.74-7.64 (m, 2H), 7.60-7.53 (m, 1H), 7.41-7.33 (m, 2H), 7.24-7.18(m, 1H), 6.09 (s, 1H), 5.52 (d, J = 8.4 Hz, 1H), 4.35-4.11 (m, 4H), 3.62(d, J = 11.2 Hz, 1H), 3.48 (dd, J = 8.4 Hz, 1H), 3.39-3.13 (m, 3H),2.95-2.70 (m, 5H), 1.66-1.50 (m, 4H), 1.37-1.06 (m, 7H), 0.77-0.56 (m,4H) ppm. 38

{7-Cyclopropyl-6- [(1-naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indanyl}(2- isonicotinoylhydrazino)- formaldehyde ¹H NMR (400 MHz,CDCl3): δ = 8.48 (br s, 2H), 7.87-7.85 (m, 1H), 7.81-7.71 (m, 4H),7.66-7.59 (m, 2H), 7.45-7.38 (m, 4H), 6.14 (s, 1H), 5.60 (d, J = 8.8 Hz,1H), 4.13 (dd, J = 15.6, 49.2 Hz, 2H), 3.69 (d, J = 11.6 Hz, 1H), 3.55(dd, J = 8.8, 11.6 Hz, 1H), 1.44-1.35 (m, 1H), 0.94- 0.85 (m, 2H),0.70-0.63 (m, 2H) ppm. 39

7-Cyclopropyl-6- [(4-methoxy-1- naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, DMSO-d6): δ = 13.35 (bs, 1H),8.21 (d, 1H, J = 2 Hz), 7.79 (d, 1H, J = 1.2 Hz), 7.56-7.49 (m, 2H),7.30 (d, 1H, J = 8.0 Hz),6.97 (d, 1H, J = 8.0 Hz), 5.32 (dd, 1H, J =1.6, 9.2 Hz), 5.23 (s, 1H), 4.34.39 (d, 1H, J = 17.2 Hz), 4.30 (d, 1H, J= 17.6 Hz), 3.98 (s, 3H), 3.79 (dd, 1H, J = 2.8, 9.0 Hz), 3.50 (dd, 1H),J = 1.6, 12 Hz), 1.76-1.70 (m, 1H), 0.98-0.86 (m, 2), 0.78-0.74 (m, 1H),0.66-0.60 (m, 1H) ppm. HRMS (ESI+) (m/z): [M + Na]+ calcd. forC23H21NNaO4S, 430.1089; found, 430.1071 40

(3R)-7-(Dimethylamino)-6-[(1- naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, Methanol-d4) δ 7.96-7.87 (m,2H), 7.84 (d, J = 8.2 Hz, 1H), 7.57-7.46 (m, 3H), 7.40 (d, J = 6.9 Hz,1H), 5.69 (s, 1H), 5.60 (d, J = 8.7 Hz, 1H), 4.45 (s, 2H), 3.92 (dd, J =12.0, 8.8 Hz, 1H), 3.69 (d, J = 12.0 Hz, 1H), 2.70 (s, 6H). 41

(3R)-5-Bromo-7- cyclopropyl-6-[(1- naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ =13.65 (br s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.99-7.95 (m, 1 H), 7.81 (d,J = 8.2 Hz, 1H), 7.68-7.56 (m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 6.77 (d, J= 7.1 Hz, 1H), 5.58 (dd, J = 1.4, 9.2 Hz, 1H), 4.74 (dd, J = 16.1, 51.0Hz, 2H), 3.89 (dd, J = 9.2, 12.0 Hz, 1H), 3.59 (dd, J = 1.7, 12.0 Hz,1H), 1.46-1.37 (m, 1H), 0.69- 0.58 (m, 2H), 0.53-0.38 (m, 2H) ppm. 42

7-Cyclopropyl-6- [(1-naphthyl)methyl]- 1,1-dioxo-4-oxo- 1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, CDCl3): δ = 13.82 (br s, 1H),8.00-7.97 (m, 1H), 7.93-7.89 (m, 2H), 7.57-7.51 (m, 3H), 7.41 (d, J =6.4 Hz, 1H), 5.73 (s, 1H), 5.33 (dd, J = 1.6, 8.8 Hz, 1H), 4.59 (ABq,2H, J = 35 Hz), 4.16- 4.04 (m, 2H), 1.89-1.82 (m, 1H), 1.24-1.19 (m,1H), 1.04-0.94 (m, 2H), 0.82-0.73 (m, 1H) ppm. HRMS calc: [M + H+]:410.1056; found: 410.1079 43

(3R)-7-Cyclopropyl- 4-oxo-6-[(2,3- xylidino)methyl]- 1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (600 MHz, MeOH-d4): δ = 6.82 (t, 1H, J = 7.8Hz), 6.47 (d, 1H, J = 7.2 Hz), 6.23 (s, 1H), 6.7 (d, 1H, J = 8.4 Hz),5.54 (d, 1H, J = 7.8), 4.48 (ABq, 2H, J = 13.1 Hz), 3.81 (dd, 1H, J = 9,12 Hz), 3.59 (dd, 1H, J = 1.2, 12 Hz), 2.24 (s, 3H), 2.13 (s, 3H),1.75-1.71 (m, 1H), 1.04-1.00 (m, 1H), 0.97-0.93 (m, 1H), 0.73-0.68 (m,2H) ppm. HRMS calc. M + H+: 371.1424; found; 317.1390 44

7-Cyclopropyl-6- [(1-naphthyl)methyl]-1- oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR (400 MHz, MeOH-d4): δ = 7.93-7.83 (m, 3H),7.52-7.46 (m, 3H), 7.39 (d, 1H, J = 6.4 Hz), 5.95 (s, 1H), 5.49 (bs,1H), 4.69 (d, 1H, J = 18 Hz), 4.60 (d, 1H, J = 18 Hz), 3.91 (dd, 1H, J =5.2, 13.6 Hz), 3.79 (dd, 1H, J = 7.6, 13.6 H), 2.03-1.96 (m, 1H),1.22-1.17 (m, 2H), 1.12-1.08 (m, 1H), 0.96-0.95 (m, 1H) ppm. MS calc:[M + H+]: 394.1, found: 394.2 45

(3R)-7-Ethoxy-6-[(1- naphthyl)methyl]- 4-oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR, 400 MHz, (DMSO) δ 1.27 (t, J = 7.0 Hz, 3H),3.58 (dd, J = 1.8, 11.9 Hz, 1H), 3.82-4.0 (m, 3H), 4.29 (dd, J =16.8,25.7 Hz, 2H), 5.34 (dd, J = 1.7, 8.9 Hz, 1H), 5.36 (s, 1H), 7.43 (dd, J= 1.1, 7.0 Hz, 1H), 7.47-7.57 (m, 3H), 7.85-7.99 (m, 3H). 46

(3R)-7-Cyclopropyl-2,2- dimethyl-6-[(1- naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid ¹H NMR (400 MHz, CDCl3): δ = 13.50(br s, 1H), 7.98-7.96 (m, 1H), 7.92-7.87 (m, 2H), 7.55-7.48 (m, 3H),7.38 (d, J = 6.8 Hz, 1H), 5.22 (s, 1H), 4.80 (s, 1H), 4.49-4.40 (m, 2H),1.73-1.67 (m, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 0.96-0.82 (m, 2H),0.73-0.60 (m, 2H) ppm. HRMS calc: [M + H+]: 406.1470; found: 406.1510 47

(3R)-6-[(1-Naphthyl)methyl]- 4-oxo-7-(trifluoromethyl)-1- thia-3a-aza-3-indancarboxylic acid ¹H NMR, 400 MHz, (DMSO) δ 3.62 (dd, J = 1.2, 11.9Hz, 1H), 3.88 (dd, J = 9.2, 11.9 Hz, 1H), 4.38 (s, 2H), 5.40 (s, 1H),5.46 (d, J = 9.2 Hz, 1H), 7.39-7.42 (m, 1H), 7.49-7.58 (m, 3H),7.74-7.80 (m, 1H), 7.89-7.94 (m, 1H), 7.96-8.01 (m, 1H). 48

(3R)-7-Isobutoxy-6-[(1- naphthyl)methyl]-4- oxo-1-thia-3a-aza-3-indancarboxylic acid ¹H NMR, 400 MHz, (DMSO) δ 0.92-0.96 (m, 6H),1.88-1.99 (m, 1H), 3.52-3.61 (m, 2H), 3.68 (dd, J = 6.4, 8.6 Hz, 1H),3.87 (dd, J = 8.9, 11.9 Hz, 1H), 4.29 (dd, J = 16.9, 23.5 Hz, 2H), 5.33(dd, J = 1.5, 8.9 Hz, 1H), 5.36 (s, 1H), 7.41-7.44 (m, 1H), 7.48-7.57(m, 3H), 7.86-7.98 (m, 3H). 49

(3R)-7-Cyclopropyl-6- [(2-methoxy-1- naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid ¹H NMR, 400 MHz, (DMSO-d6, 400MHz): δ = 13.33 (bs, 1H), 7.97 (d, 1H, J = 8.8 Hz), 7.92 (dd, 1H, J =1.2, 8.4 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.53 (d, 1H, J = 9.2 Hz), 7.47(ddd, 1H, J = 1.2, 6.8, 8.5 Hz), 7.39-7.34 (m, 1H), 5.29 (dd, 1H, J =1.6, 9.2 Hz), 4.94 (s, 1H), 4.42 (d, 1H, J = 18 Hz), 4.33 (d, 1H, J = 18Hz), 3.91 (s, 3H), 3.79 (dd, 1H, J = 2.8, 9.2 Hz), 3.49 (dd, 1H, J =1.6, 11.6 Hz), 1.91-1.85 (m, 1H), 1.09-0.97 (m, 2H), 0.83-0.78 (m, 1H),0.73-0.67 (m, 1H) ppm. 50

(3R)-7-(Cyclopropylmethoxy)- 6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza- 3-indancarboxylic acid ¹H NMR, 400 MHz, (DMSO) δ0.24-0.30 (m, 2H), 0.51-0.57 (m, 2H), 1.11-1.24 (m, 1H), 3.57 (dd, J =1.7, 11.9 Hz, 1H), 3.71 (dABq, J = 7.2, 14.5 Hz, 2H), 3.87 (dd, J = 8.9,11.9 Hz, 1H), 4.31 (dd, J = 16.6, 28.4 Hz, 2H), 5.31-5.35 (m, 2H),7.41-7.45 (m, 1H), 7.47-7.57 (m, 3H), 7.85-7.99 (m, 3H). 51

7-Cyclopropyl-6-[(2-methyl-1- aza-2-bora-1H-naphth-5-yl)methyl]-4-oxo-1- thia-3a-aza-3- indancarboxylic acid 52

7-Cyclopropyl-6- [(2-methyl-1-aza-2- bora-1H-naphth-5-yloxy)methyl]-4-oxo- 1-thia-3a-aza-3- indancarboxylic acid 53

7-Cyclopropyl-6- [(2-methyl-1-aza-2- bora-1H-naphth-8-yl)methyl]-4-oxo-1- thia-3a-aza-3- indancarboxylic acid 54

7-Cyclopropyl-6- [(2-methyl-1-aza-2- bora-1H-naphth-8-yloxy)methyl]-4-oxo- 1-thia-3a-aza-3- indancarboxylic acid

INTERMEDIATES Benzyl(4R)-2-(cyclopropylmethyl)Δ²-1,3-thiazoline-4-carboxylate

Et₃N (0.28 mL, 206 mg, 2.0 mmol) was added, at RT, to a solution of(R)-Cysteine benzyl ester hydrochloride (506 mg, 2.0 mmol) and2-cyclopropyl-1-ethoxy-1-ethanimine hydrochloride (368 mg, 2.2 mmol) indry CH₂Cl₂ (20 mL). Precipitation started within minutes after additionof Et₃N. The reaction mixture was stirred at RT for 18 h and dilutedwith CH₂Cl₂. NaHCO₃ (sat aq, 10 mL) was added and the phases wereseparated. The aqueous phase was extracted with CH₂Cl₂ and the combinedorganic phases were dried (Na₂SO₄), filtered and concentrated in vacuoto afford 587 mg pale yellow oil. Purification by column chromatography(Biotage 50 g, 10-30% EtOAc in heptane) afforded 324 mg (58%) of theproduct as a pale yellow oil. ¹H NMR (600 MHz, CHCl₃): δ 7.35 (m, 5H),5.24 (dd, J=12.6, 22.8 Hz, 2H), 5.10 (m, 1H), 3.53 (m, 2H), 2.46 (m,2H), 0.98 (m, 1H), 0.57 (m, 2H), 0.22 (m, 2H).

5-{1-Hydroxy-2-[m-(trifluoromethyl)phenyl]ethylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione

3-(Trifluoromethyl)phenylacetic acid (1.22 g, 6.0 mmol), Meldrum's acid(908 mg, 6.3 mmol) and DMAP (770 mg, 6.3 mmol) was dissolved in CH₂Cl₂(20 mL) and cooled to 0° C. DCC (1 M in CH₂Cl₂, 7.8 mL, 7.8 mmol) wasadded drop-wise to the cooled solution that was stirred at 0° C. for 2 hand then over night at RT. KHSO₄ (6% aq. 12 mL) was added and theresulting precipitate was filtered off. The filtrate was washed withKHSO₄ (6% aq. 5×20 mL), H₂O (20 mL), brine (20 mL), dried (Na₂SO₄) andconcentrated in vacuo. The afforded pink solid as suspended in CH₂Cl₂,the suspension as filtered and concentrated in vacuo to afford 2.03 g ofa dark purple solid. This was the titled product, although not 100%pure. However, the purity was good enough to continue with.

¹H NMR (400 MHz, CHCl₃): δ 15.37 (br s, 1H), 7.67-7.62 (m, 1H),7.61-7.53 (m, 2H), 7.48-7.42 (m, 1H), 4.48 (s, 2H), 1.73 (s, 6H)

Benzyl(3R)-7-cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylate

TFA (84 μL, 0.11 mmol) was added to a solution of Benzyl(4R)-2-(cyclopropylmethyl)Δ²-1,3-thiazoline-4-carboxylate (151 mg, 0.55mmol) and5-{1-Hydroxy-2-[m-(trifluoromethyl)phenyl]ethylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione(543 mg, 1.65 mmol) in DCE (15 mL). Heated by MW at 120° C. for 2 min 30sec. The reaction mixture was cooled to RT, diluted with CH₂Cl₂ (40 mL)and NaHCO₃ (sat aq, 5 mL) and H₂O (5 mL) were added. The phases wereseparated and the aqueous phase extracted with CH₂Cl₂ (3×15 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo toafford 586 mg brown oil. Two consecutive purifications by columnchromatography (first Biotage 50 g, 30-85% EtOAc in heptane and then 10g Biotage) gave 69 mg (26%) of the product as pale yellow amorphoussolid. ¹H NMR (600 MHz, CHCl₃): δ 7.49 (m, 1H), 7.45 (m, 1H), 7.40 (m,1H), 7.34-7.29 (m, 6H), 5.99 (s, 1H), 5.64 (dd, 1.8, 8.4 Hz, 1H), 5.22(dd, 12, 19 Hz, 2H), 4.07 (d, 15.6 Hz, 1H), 3.98 (d, 16 Hz, 1H), 3.63(dd, 9.0, 12.0 Hz, 1H), 3.47 (dd, 2, 12 Hz, 1H), 1.36 (m, 1H), 0.92 (m,1H), 0.85 (m, 1H), 0.62 (m, 2H) ppm.

Methyl(3R)-7-cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylate

¹H NMR (400 MHz, CHCl₃): δ 7.48-7.52 (m, 1H), 7.35-7.46 (m, 3H),5.99-6.01 (m, 1H), 5.61 (dd, J=2.3, 8.6 Hz, 1H), 4.09 (d, J=16.0 Hz,1H), 3.99 (d, J=16.0 Hz, 1H), 3.80 (s, 3H), 3.66 (dd, J=8.6, 11.6 Hz,1H), 3.50 (dd, J=2.3, 11.6 Hz, 1H), 1.33-1.42 (m, 1H), 0.83-0.97 (m,2H), 0.60-0.70 (m, 2H).

Biology

Biofilm Inhibition of Mycobacterium tuberculosis

The compounds of Examples 1-50 were dissolved in DMSO and tested forbiofilm inhibition of Mycobacterium tuberculosis, as described below atconcentrations of 10 microM, 25 microM, 50 microM and/or 100 microM. Themeasurement of biofilm inhibition was made by ocular inspection of thetested tuberculosis bacteria. For each concentration, three or moremeasurements were made and then an average value was calculated. Foreach measurement, the biofilm inhibition was considered to be complete,partial or not taking place. Complete or full biofilm inhibition meansthat none of the tested tuberculosis bacteria exhibit biofilm, i.e. theinhibition is 100%. Partial biofilm inhibition means the tuberculosisbacteria exhibit a disrupted and/or limited biofilm. For simplicity ofcalculation, an inhibition value of 50% was set when partial biofilminhibition was observed. Biofilm inhibition was considered not to takeplace if all tested tuberculosis bacteria exhibited biofilm, i.e.biofilm inhibition was 0%.

Some of the compounds of Examples 1-54 were also tested to find aconcentration at which full biofilm inhibition took place. The result isshown in Table 2 below, and all compounds tested in this way were foundto have satisfactory biofilm inhibition, i.e. as shown in the column“Full Biofilm inhibition at μM” in Table 2.

The measurement of biofilm inhibition of Mycobacterium tuberculosis tookplace as follows. Bacterial biofilms were inoculated with stationaryphase planktonic cultures of Mycobacterium tuberculosis Erdman intoSauton's media (available from HiMedia laboratories) at a 1:100 dilutionand incubated at 37° C. in 5% CO₂. Culture vessels were closed tightlyto restrict oxygen for 3 weeks, and then vented. When a compound ofExamples 1-50 was included, it was added to biofilm cultures at the timeof inoculation. In all assays performed with a compound of Examples1-50, control samples were treated with DMSO vehicle. It was checkedthat at the concentrations used, there was no effect of DMSO itself onbiofilm formation or Mtb physiology.

Crystal Violet Staining.

Biofilms were cultured as just described in 96-well plates in thepresence and absence of Example 1-50, media was aspirated, and plateswere gently washed with water 3 times. Plates were stained with 0.5%crystal violet for 15 minutes, washed 3 times in water, and air dried.To quantify staining, 45% acetic acid was used to destain each well,diluted 1:10 in formalin, and read at ODλ₆₀₀.

Stress and Tolerance Assays in Biofilm Conditions.

Mtb was grown in biofilm-forming conditions in Sauton's medium in thepresence and absence of Example 1-50. After 3 weeks, seals on thevessels were opened, and concentrated solutions of antibiotics or H₂O₂were pipetted underneath the surface of the culture. After 2 weeks ofexposure to the indicated stress, bacteria were harvested from eachwell, centrifuged to pellet, and resuspended in 1% Tween 80 inphosphate-buffered saline (PBS). Glass beads were added to each tube andtubes were shaken overnight at room temperature to disassociatebacteria. Serial dilutions were plated to enumerate CFUs.

Stress and Tolerance Assays in Aerated, Planktonic Conditions.

For aerated growth curves, Mtb was inoculated into Sauton's mediumcontaining 0.05% Tween 20 at an opticial density of 0.08. DMSO(control), 25 μM of the compound of Example 1, or 0.25 g/ml INH wereadded as indicated. Changes in OD_(λ600) were monitored. After ten daysof planktonic growth, cultures were plated on 7H11 agar plates toenumerate bacterial CFUs. The 7H11 agar plates (available fromSigmaAldrich). For pH and nitrosative stress assays, Mtb was grown in inSauton's medium containing 0.05% Tween 80 in the presence and absence ofMTIs and at the indicated pH and NaNO concentrations at 37° C. At theindicated times, cultures were pipetted to mix and a small sample wasremoved to plate for CFUs.

The results of the biofilm inhibition measurements are shown in Table 2.

TABLE 2 Average % Inhibition at Example 10 25 50 100 Full Biofilm NumberμM μM μM μM inhibition at μM  1 100 100 2.5 μM, 7.5 μM, 2.5 μM, 10 μM  263 100 75 25 μM, 25 μM  3 100 100 100 50 μM  4 100 100 100 25 μM, 25 μM,25 μM  5 100 100 100 5 μM, 5 μM  6 50 88 100 100 30 μM, 30 μM, 30 μM  750 100 100 25 μM, 25 μM, 25 μM  8 75 63 75 25 μM, 25 μM  9 50 87 87 25μM, 25 μM 10 69 100 100 11 75 38 88 12 12 50 87 13 62 75 100 50 μM, 50μM 14 0 88 100 15 87 100 100 50 μM 16 25 62 100 17 25 38 100 50 μM, 50μM 18 12 12 38 19 0 0 88 100 20 75 100 100 25 μM, 25 μM, 21 12 100 10022 38 25 23 12 50 24 12 62 25 12 50 26 50 μM 27 75 88 100 25 uM, 25 μM,25 μM 28 50 μM, 50 μM 29 50 μM, 50 μM 30 50 uM 31 100 32 50 μM, 50 μM 3325 μM, 25 μM, 25 μM 34 25 30 μM, 30 μM, 30 μM 35 25 75 50 μM, 50 μM 36100 100 100 37 100 100 100 38 100 100 100 25 μM, 25 μM, 25 μM 39 50 100100 40 50 100 50 41 25 62 88 100 42 50 12 12 43 50 100 44 25 75 100 4550 25 46 62 38 47 100 >50 μM 48 50 49 25 μM, 25 μM, 25 μM 50 25

Treatment of Mycobacterium tuberculosis Bacteria with Isoniazid in theAbsence or Presence of the Compound(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicAcid, i.e. the Compound of Example 1

FIG. 5 a shows an agar plate containing 0.05% DMSO and inoculated with1.959×10⁸ CFU of Mycobacterium tuberculosis and a disk spotted with 5 μlof water placed onto the plate at the time of inoculation. Photo wastaken after 4 weeks of incubation at 37° C. in 5% CO₂.

FIG. 5 b shows an agar plate containing 0.05% DMSO and inoculated with1.959×10⁸ CFU of Mycobacterium tuberculosis and a disk spotted with 5 μlof 0.5 mg/ml INH placed onto the plate at the time of inoculation. Photowas taken after 4 weeks of incubation at 37° C. in 5% CO₂.

FIG. 5 c shows an agar plate containing a DMSO solution of 25 μM(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid and inoculated with 1.959×10⁸ CFU of Mycobacterium tuberculosis anda disk spotted with 5 μl of water placed onto the plate at the time ofinoculation. Photo was taken after 4 weeks of incubation at 37° C. in 5%CO₂.

FIG. 5 d shows an agar plate containing a DMSO solution of 25 μM(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid and inoculated with 1.959×10⁸ CFU of Mycobacterium tuberculosis anda disk spotted with 5 μl of 0.5 mg/ml INH placed onto the plate at thetime of inoculation. Photo was taken after 4 weeks of incubation at 37°C. in 5% CO₂.

For FIG. 6 , Mtb was innoculated into Sauton's medium in the presence ofthe compound of Example 1 and the compound of Example 19, 25 μMrespectively, and in the absence of the compound of Example 1 and thecompound of Example 19, respectively, and sealed to restrict oxygen.After 3 weeks, seals on the vessels were opened, and INH at theindicated concentration was pipetted underneath the surface of theculture. After 2 weeks of exposure to the INH, bacteria were harvestedfrom each well, centrifuged to pellet, and resuspended in 1% Tween 80 inphosphate-buffered saline (PBS). Glass beads were added to each tube andtubes were shaken overnight at room temperature to disassociatebacteria. Serial dilutions were plated to enumerate colony formingunits. FIG. 6 shows the ratio of colony forming units of treated anduntreated tuberculosis bacteria as a function of the concentration ofadded isoniazid, added combination of isoniazid and the compound ofExample 1 and added combination of isoniazid and the compound of Example19, respectively. In the graph “Control” means that only isoniazid andDMSO were added, “Example 1” means that a combination of isoniazid andthe compound of Example 1 was added, and “Example 19” means that acombination of isoniazid and the compound of Example 19 was added. Inthe graph, the concentration refers to the concentration of isoniazid.The concentration of the compound of Example 1 and Example 19,respectively, was 50 microM and 25 microM, respectively. It can be seenthat tuberculosis bacteria remained when treatment was performed withisoniazid alone (control). However, no tuberculosis bacteria could bedetected when isoniazid was used in combination with the compound ofExample 1 or in combination with the compound of Example 19. In thisdocument, ND stands for none detected, i.e. tuberculosis bacteria couldnot be detected. The following conclusions can be drawn from the aboveexperiments.

Isoniazid alone, i.e. in the absence of(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid and the compound of Example 19, did not eradicate Mycobacteriumtuberculosis.

(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid alone, i.e. in the absence of isoniazid, did not eradicateMycobacterium tuberculosis.

A combination of isoniazid and the compound of example 1 (i.e.(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid) eradicated Mycobacterium tuberculosis.

A combination of isoniazid and the compound of Example 19 (i.e.8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid) eradicated Mycobacterium tuberculosis.

Comparison of Treatment of Wild-Type Mycobacterium tuberculosis Bacteriawith Treatment of Mycobacterium tuberculosis Bacteria Characterized byMutations in the Catalase katG

Treatment of Erdman Wild-Type Mycobacterium tuberculosis bacteria

The effect of(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid (Example 1) on INH sensitivity was demonstrated by incubatingplanktonic, aerated Mtb cultures containing 25 μM Example 1 and/or 0.25μg/ml INH, which is approximately ten times the MIC of INH (0.02-0.06μg/ml), and monitoring growth as changes in ODλ₆₀₀ overtime. Acomparison was made with a control, which contained no compound ofExample 1 and no INH.

FIG. 8 a shows that under these conditions, Example 1 alone slowed thegrowth of Mtb, increasing the doubling time from 29 hours to 52 hours.demonstrating that Example 1 has a relatively minor but significantimpact on Mtb growth. Treatment with INH or the INH+Example 1combination completely inhibited Mtb growth, as measured by ODλ₆₀₀.

FIG. 8 b shows the determination of effects on Mtb viability. Sampleswere harvested from each growth curve culture 240 hours post inoculationand plated to enumerate colony forming units (CFU). Treatment withExample 1 resulted in 7.6 fold less Mtb in the culture as compared tocontrols, supporting that this compound alone has some growth inhibitoryproperties. Although treatment with INH alone or the combinationINH+Example 1 inhibited growth as measured by ODλ₆₀₀, only thecombination of INH+Example 1 eliminated all of the culturable bacteria.In contrast, several thousand CFU/ml remained viable in the culturestreated with INH alone for 10 days, which reflects the bacteriostaticnature of this antibiotic.

FIGS. 8 c-8 f show a lawn of the WT strain plated on agar. FIG. 8 cshows the experiment run as a control, i.e. no compound of example 1 andno INH were present. FIG. 8 d shows the experiment run in the presenceof INH. FIG. 8 e shows the experiment run in the presence of Example 1.FIG. 8 f shows the experiment run in the presence of the combination ofExample 1 and INH. It was observed that only the combination of thecompound of Example 1 and INH eradicated the WT Mtb.

The results shown in FIGS. 8 a and 8 b demonstrate that INH+Example 1synergize with each other to result in a bactericidal outcome. Theconclusion is that this combination can shorten the treatment time.

Treatment of Mycobacterium tuberculosis INH-Resistant Bacteria with aMutation in the Catalase katG

This experiment was performed in analogy with the experiment above inwhich WT Mtb was used, but Mtb with a mutation in the catalase katG wasused instead of WT Mtb. The INH-resistant strain was derived by playingthe Erdman WT strain onto plates containing isoniazid and selecting forresistant colonies of bacteria. Before use the katG gene was sequencedto determine the mutation.

Mtb resistance to INH generally occurs by mutations in the catalasekatG. When an Mtb isolate with a frameshift at amino acid 6 in katG(katGFSAA6) was grown in planktonic cultures in the presence or absenceof 25 μM of the compound of Example 1, 0.25 μg/ml of INH, or acombination of INH and the compound of Example 1. A comparison was madewith a control, which contained no compound of Example 1 and no INH.

FIG. 9 a shows that the compound of Example 1 alone reduced the doublingtime of the katGFSAA6 strain from 23 to 48 hours. This is similar towhat was observed in the WT Mtb (FIG. 8 a ). The katGFSAA6 strain wassignificantly more resistant to INH alone and was able to grow in thepresence of INH with a doubling time of 55 hours, whereas WT Mtb growthwas undetectable in planktonic cultures the presence of INH (FIG. 8 a ).

FIG. 9 b , however, shows that in the presence of the combinationINH+Example 1, the katGFSAA6 strain was unable to replicate based onODλ₆₀₀ and when we plated bacteria from these planktonic cultures after10 days, no culturable CFU remained.

FIGS. 9 c-9 f show a lawn of the katGFSAA6 strain plated on agar. FIG. 9c shows an experiment run as a control, i.e. no compound of example 1and no INH were present. FIG. 9 d shows the experiment run in thepresence of INH. FIG. 9 e shows the experiment run in the presence ofthe compound of Example 1. FIG. 9 f shows the experiment run in thepresence of the combination of the compound of Example 1 and INH. It wasobserved that for experiments containing Example 1 or INH alone, themutant was able to grow (FIGS. 9 d and 9 e ). In contrast, as shown inFIG. 9 f , the katGFSAA6 strain did not grow on agar in the presence ofINH+Example 1, demonstrating that these bacteria are sensitive to thiscombination. The inability to isolate colonies on plates containingINH+Example 1 indicates that the combination is toxic for all katGmutants that normally grow in the presence of INH.

Together these data show that the combination of INH+Example 1 blocksthe growth and survival of INH-resistant katG mutants, thus restoringthe sensitivity of katG mutants to INH treatment.

Further Comments Regarding the Results Shown in FIG. 8 and FIG. 9 ,Respectively.

FIGS. 8 a-8 b show the results for WT Mtb and FIG. 9 a-9 b katGFSAA6Mtb, respectively, grown in planktonic conditions in the presence of0.25 μg/ml INH, 25 μM Example 1 or a combination. Culture absorbance wasmeasured overtime and CFUs were plated at 10 days post inoculation.Error bars represent the range of two samples. Significance of thedifferences was determined by calculating P values by ANOVA. *P<0.05.**P<0.01. ***P<0.001. ****P<0.0001. (B, E) ND=Not detected; Limit ofDetection=1 CFU/ml. (c) The WT or (f) katGFSAA6 Mtb strain was platedonto Sautons agar plates containing INH, Example 1, or a combination ofINH+Example 1. It was concluded that a combination of INH and thecompound of Example 1 eradicated WT Mtb and also eradicated Mtb with amutation in katGFSAA6.

1. A composition comprising: (i) a drug against tuberculosis, or apharmaceutically acceptable salt thereof; and (ii) a compound of FormulaII

or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom the group consisting of: a) C(O)OH, b) tetrazolyl, c) CH₂OH, d)C(O)NR_(6a)R_(6b), e) C(O)NHSO₂R₇, f) C(O)OR₈, g) NH₂, h) H,

R₂ is selected from the group consisting of: a) H, b) Cl, F, Br or I, c)CH₂OH, d) C₁-C₄alkyl, and e) NY₁Y₂, R₃ is selected from the groupconsisting of: a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, eachindependently substituted with 0, 1, 2 or 3 substituents selected fromthe group consisting of methyl, fluoro, chloro, bromo, cyano, andmethoxy, b) phenyl substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of methyl, fluoro,chloro, cyano, and trifluoromethyl, c) aminophenyl substituted with 0,1, 2 or 3 substituents independently selected from the group consistingof methyl, fluoro, chloro, and trifluoromethyl, d)2-(3-methyl)phenylmethylene, e) benzothiophen-2-yl, f) H or C₁-C₄-alkyl,i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and j)2-methyl-1-aza-2-bora-1H-naphth-5-yl, R₄ is selected from the groupconsisting of: a) C₁-C₄alkyl substituted by 0, 1, 2, 3 or 4 fluoro; b)C₃-C₆cycloalkyl, c) C₁-C₄alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,d) C₃-C₆cycloalkoxy, e) a 3-, 4-, 5- or 6-membered heterocycle, f)N-methyl 3-indolyl, and h) NR₉R₁₀, R₅ is selected from the groupconsisting of: a) H, b) phenyl substituted with 0, 1, 2 or 3 methylgroup(s), c) benzyl, d) thienyl, e) C₁-C₄alkoxy, and f) 3-, 4-, 5- or6-membered heterocycle, and in the above definitions: R_(6a) is selectedfrom the group consisting of H and C₁-C₄alkyl, R_(6b) is selected fromthe group consisting of H, C₁-C₄alkyl, C₁-C₄alkoxy, andisonicotinoylamino; R₇ is C₁-C₄alkyl or phenyl, R₈ represents2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl), R_(9a) representsC₁-C₄alkyl, R_(9b) represents C₁-C₄alkyl, R₁₀ represents C₁-C₄alkyl, orR₉ and R₁₀ together form CH₂(CH₂)_(m)CH₂, Y₁ and Y₂ each independentlyrepresents hydrogen, methyl, CH₃S(O)₂ or C(O)CH₃, or Y₁ and Y₂ togetherform CH₂CH₂CH₂CH₂ or CH₂CH₂CH₂CH₂CH₂, m is 1, 2 or 3, and X is S, SO orSO₂.
 2. The composition according to claim 1, wherein the compound ofFormula II is a compound of Formula IIa or Formula IIb:

wherein R₁, R₂, R₃, R₄, R₅ and X are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 3. The composition accordingto claim 1, wherein the compound of Formula II is a compound of FormulaIIa51:

wherein R₁, R₂, R₃, R₄ and X are as defined in claim 1, or apharmaceutically acceptable salt thereof. 4.-7. (canceled)
 8. Thecomposition according to claim 1, wherein X is S or SO.
 9. Thecomposition according to claim 1, wherein R₁ is C(O)OH, tetrazolyl, orC(O)NHSO₂R₇.
 10. The composition according to claim 1, wherein R₂ is H.11. The composition according to claim 1, wherein R₃ is selected fromthe group consisting of: a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, eachindependently substituted with 0, 1, 2 or 3 substituents selected fromthe group consisting of methyl, fluoro, chloro, cyano, and methoxy, andb) phenyl substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of methyl, fluoro, chloro, cyano, andtrifluoromethyl.
 12. The composition according to claim 1, wherein R₃ isselected from the group consisting of: 1-naphtyl, 2-naphtyl,4-methyl-1-naphtyl, 4-fluoro-1-naphtyl, 4-bromo-1-naphtyl,4-methoxy-1-naphtyl, 2-methoxy-1-naphtyl, 2-methoxy-1-naphtyl,1-naphtyloxy, 3-methylphenyl, 2,3-dimethylphenyl,2-fluoro-5-methylphenyl, 2,3-dichlorophenyl,2-(3-methyl)phenylmethylene; 2,3-xylylamine, 3-trifluoromethylphenyl,and benzothipohene-2-yl
 13. The composition according to claim 1,wherein R₃ is 1-naphtyl.
 14. (canceled)
 15. The composition according toclaim 14, wherein R₄ is cyclopropyl.
 16. The composition according toclaim 1, wherein R₅ is H or phenyl substituted with 0, 1, 2 or 3 methylgroup(s).
 17. The composition combination according to claim 1, whereinthe compound of Formula II is selected from:(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid,(3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde,(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone,5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid,5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid,(3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,(3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylicacid,5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid,8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylicacid,(3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide,{(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde,(3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid, (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,{(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde,(3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylicacid,7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylicacid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,(3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,(2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylicacid,(2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylicacid, 2-{2-[1-(Hydroxymethyl)propylamino]ethylamino}butyl7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate,{7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde,7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid, or a pharmaceutically acceptable salt of any of the foregoingcompounds.
 18. (canceled)
 19. (canceled)
 20. The composition accordingto claim 1, wherein the compound of Formula II is selected from thegroup consisting of:(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylicacid, and(3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic,or a pharmaceutically acceptable salt of any of the foregoing compounds.21. (canceled)
 22. (canceled)
 23. (canceled)
 24. The compositionaccording to claim 1, wherein the drug against tuberculosis is at leastone of the following: isonicotinylhydrazide, bedaquiline, ethionamide,pretomanid, 4-aminosalisalicylic acid, rifampicin, pyrazinamide, orethambutol.
 25. (canceled)
 26. The composition according to claim 24,wherein the drug against tuberculosis is isonicotinylhydrazide and/orbedaquiline. 27.-57. (canceled)
 58. A compound which is selected from:7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylicacid, 2-{2-[1-(Hydroxymethyl)propylamino]ethylamino}butyl7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate,{7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde,7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,(3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-)-aza-2-bora-H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid,7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylicacid, or a pharmaceutically acceptable salt of any of the foregoingcompounds. 59.-61. (canceled)
 62. A kit comprising: i) an effectiveamount of a drug against tuberculosis, or a pharmaceutically acceptablesalt thereof; ii) an effective amount of a compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom the group consisting of: a) C(O)OH, b) tetrazolyl, c) CH₂OH, d)C(O)NR_(6a)R_(6b), e) C(O)NHSO₂R₇, f) C(O)OR₈, g) NH₂, h) H,

R₂ is selected from the group consisting of: a) H, b) Cl, F, Br or I, c)CH₂OH, d) C₁-C₄alkyl, and e) NY₁Y₂, R₃ is selected from the groupconsisting of: a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, eachindependently substituted with 0, 1, 2 or 3 substituents selected fromthe group consisting of methyl, fluoro, chloro, bromo, cyano, andmethoxy, b) phenyl substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of methyl, fluoro,chloro, cyano, and trifluoromethyl, c) aminophenyl substituted with 0,1, 2 or 3 substituents independently selected from the group consistingof methyl, fluoro, chloro, and trifluoromethyl, d)2-(3-methyl)phenylmethylene, e) benzothiophen-2-yl, f) H or C₁-C₄-alkyl,i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and j)2-methyl-1-aza-2-bora-TH-naphth-5-yl, R₄ is selected from the groupconsisting of: a) C₁-C₄alkyl substituted by 0, 1, 2, 3 or 4 fluoro; b)C₃-C₆cycloalkyl, c) C₁-C₄alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,d) C₃-C₆cycloalkoxy, e) a 3-, 4-, 5- or 6-membered heterocycle, f)N-methyl 3-indolyl, and h) NR₉R₁₀, R₅ is selected from the groupconsisting of: a) H, b) phenyl substituted with 0, 1, 2 or 3 methylgroup(s), c) benzyl, d) thienyl, e) C₁-C₄alkoxy, and f) 3-, 4-, 5- or6-membered heterocycle, and in the above definitions: R_(6a) is selectedfrom the group consisting of H and C₁-C₄alkyl, R_(6b) is selected fromthe group consisting of H, C₁-C₄alkyl, C₁-C₄alkoxy, andisonicotinoylamino; R₇ is C₁-C₄alkyl or phenyl, R₈ represents2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl), R_(9a) representsC₁-C₄alkyl, R_(9b) represents C₁-C₄alkyl, R₁₀ represents C₁-C₄alkyl, orR₉ and R₁₀ together form CH₂(CH₂)_(m)CH₂, Y₁ and Y₂ each independentlyrepresents hydrogen, methyl, CH₃S(O)₂ or C(O)CH₃, or Y₁ and Y₂ togetherform CH₂CH₂CH₂CH₂ or CH₂CH₂CH₂CH₂CH₂, m is 1, 2 or 3, and X is S, SO orSO₂: and iii) optionally instructions of use.
 63. The kit of claim 62,wherein the kit comprises instructions for use.
 64. A kit comprising: i)an effective amount of the composition of claim 1; and ii) optionallyinstructions of use.
 65. The kit of claim 64, wherein the kit comprisesinstructions for use.